Further studies on the effect of cyclosporin A on the course of Paragonimus infection in rats

Cyclosporin A administered to Schistosoma mansoni-infected mice at around day 20 of infection reduces the worm burden by greater than 60%, as assessed by portal perfusion on days 28 and 86. Those worms recovered at perfusion have been examined by light and electron microscopy for drug-induced changes in morphology. Gross parasite damage was characterized by massive bolus formation and subsequent herniation of the gut. This event was attributed to the abnormal accumulation of crystalline structures in the lumen; the crystals were closely associated with lipid droplets, and were shown by X-ray micro-analysis to contain iron. Such crystals were seen only rarely in the intestines of control worms, but they too gave small iron peaks when examined by X-ray micro-analysis. In some drug-treated worms the caecal epithelium had ruptured, thereby releasing luminal contents throughout the worm body. In addition, herniations of the gut were seen protruding through the tegument causing surface deformation and disruption of tegumental and parenchymal tissues. The structural integrity of the worm was ultimately compromised allowing access to cytotoxic effector cells of the host. The combined effects of drug action and cellular cytotoxicity presumably account for the very significant levels of worm killing achieved by CsA treatment of the host.

Section: Introductionmentioning

confidence: 99%

Schistosoma mansoni:morphology and ultrastructure of adult worms recovered from cyclosporin A-treated mice

Munro

McLaren

1990

“…Unpublished data show that the drug exerts powerful but selective action against juvenile Fasciola hepatica in rats and in vitro (Penlington et al in preparation). The effects of CsA on Paragonimus miyazakii and P. ohirai in rats vary according to treatment regime (see below) (Hashiguchi & Okamura, 1988. These and other models require further exploration to determine whether CsA is generally toxic to trematodes or whether its activity range is rather more narrow.…”

Section: Anthelmintic Activitymentioning

confidence: 99%

“…The effects of CsA on Paragonimus miyazakii in rats are dependent upon timing of drug administration relative to infection age. Treatment around time of infection results in increased worm growth and accelerated maturation while later drug treatment (at 15-19 days post-infection) brings about decreased recoveries of worms and reduced cyst formation in the lungs (Hashiguchi & Okamura, 1988). In the case of the related parasite, P. ohirai in rats (Hashiguchi & Okamura, 1989), CsA is exclusively anthelmintic regardless of time of treatment.…”

Section: Combined Immunomodulatory and Antiparasitic Activity Of Csamentioning

confidence: 99%

Cyclosporin A: antiparasite drug, modulator of the host-parasite relationship and immunosuppressant

Chappell

Wastling

1992

Cyclosporin A (CsA), a cyclic undecapeptide with powerful properties of immunosuppression, acts on parasitic infections in laboratory animals in various ways. The outcome of drug administration in vivo varies with timing of treatment relative to infection, route of administration, dose and number of treatments applied. CsA is clearly antiparasitic against malaria, schistosomes, adult tapeworms, metacestodes and filarial nematodes. By contrast, it acts as an immunomodulator against trypanosomes and Giardia, by exacerbating infection; in the case of Leishmania spp. the drug acts variously. In some other infections CsA acts both as an antiparasite drug and as an immunosuppressant (Toxoplasma, avian coccidiosis and gastrointestinal nematodes). This range of activities is reviewed and possible modes of action discussed in the light of emerging data on in vitro drug activity and on putative receptor binding. The potential value of a non-immunosuppressive analogue of CsA in the control of parasitic infections of humans and domestic animals is considered but this paper lays particular stress on the seminal role of CsA as a laboratory tool.

“…In addition to its immunosuppressive activities, CsA is also reported to exhibit anti-parasitic activity; these effects have been shown in a variety of host-parasite experimental systems. The anti-malarial activity of CsA has been demonstrated in mice infected with Plasmodium berghei, P. chabaudi or P. yoelii (Nickell, Scheibel & Cole, 1982;Thommen-Scott, 1981), while CsA-treated Mastomys and rats, show significant protection against filariae and Paragonimus respectively (Bout, Haque & Capron, 19846;Zahner & Schultheiss, 1987;Hashiguchi & Okamura, 1988). Several groups have shown that treatment of mice with CsA results in both immediate and prophylactic effects against Schistosoma mansoni infection (Bout, Deslee & Capron, 1984a, 1986Bueding, Hawkins & Cha, 1981;Nilsson et al 1985;Chappell et al 1987;Smith et al 1988), and that the anti-parasitic effects are not linked to the immunosuppressive activity of the drug.…”

Section: Introductionmentioning

confidence: 99%

Toxicity of cyclosporin A (CsA) against developmental stages of Schistosoma mansoni in mice

Munro

McLaren

1990

It has been shown elsewhere that the immunosuppressive drug cyclosporin A (CsA) exerts profound schistosomicidal activity when given to infected mice via a multiple administration regime. We show here that a single treatment regime also effects significant reductions in worm burden. Moreover, drug efficacy is maintained at CsA concentrations shown to be subimmunosuppressive in other systems. Subcutaneous treatment effected higher levels of schistosomicidal activity than intraperitoneal or oral treatment, irrespective of whether the drug was given prior to or during infection. Topical application of CsA to the skin site of cercarial penetration, prior to infection resulted in no reduction in worm burden. Systemic release of CsA from a slowly adsorbed, oil-based drug-vehicle combination effected greater levels of killing than when CsA was dissolved in an aqueous drug vehicle. All developmental stages of Schistosoma mansoni were susceptible to killing by a single dose of CsA but, in the case of liver-stage worms, an increased concentration of drug and a longer period between treatment and portal perfusion were needed for killing to be measurable as a reduction in worm numbers.